Since the discovery of antibiotic substances and their use against microbes, bacteria have evolved to defend themselves by acquiring resistances. Especially in hospitals where bacteria are exposed to a wide array of antibacterial substances, strains arose that are multiresistant. A prominent example for this is the multiresistant Staphylococcus aureus (MRSA) against which vancomycin used to be a reliable cure, until the strains Vancomycin-Intermediate/Resistant Staphylococcus aureus (VISA /VRSA) started to appear, which are also resistant against this last defence.
The mechanisms of resistance are usually tightly intertwined with the mode of action of the antibiotic. Therefore, the resistance against one representative of a certain antibiotics class yields to resistance against the entire group with the same mode of action. This is why it is not only necessary to have an ongoing search for new antibiotic substances, but to also find and use new antibacterial targets enforcing new mechanisms of action.
In the past the mode of action for several antibacterial compounds was revealed to be inter alia the targeting of riboswitches. To date metabolite analogues have been described which modulate thiamine pyrophosphate (TPP), lysine, flavin mononucleotide (FMN) or purine riboswitches.
Riboswitches have appeared as one of these new promising targets for antibacterial defence. Riboswitches, which regulate 2-4% of all bacterial genes, are found in the 5′-untranslated region (5′ UTR) of bacterial mRNA and consist of an aptamer and an expression domain. Upon metabolite binding, a change in secondary structure leads to termination of transcription or inhibition of translation initiation. Amongst them the glmS riboswitch (glucosamine-6-phosphate synthetase riboswitch) which is predicted to exist in at least 18 Gram-positive organisms has an exceptional mechanism of regulation. The glmS riboswitch binds glucosamine-6-phosphate to regulate glucosamine-6-phosphate synthetase (glmS) genes. Once glucosamine-6-phosphate binds, this riboswitch acts as a ribozyme, resulting in cleavage of the 5′ end of the riboswitch.
Antibiotic resistance creates a permanent need for new antibacterial targets. Thus, it would be desirable to provide compounds that target the glmS riboswitch and exhibit antimicrobial activity.
Therefore, the object underlying the present invention was to provide compounds that are usable as antibiotic.